The long term goal of our laboratory is to understand the mechanisms of peripheral T cell tolerance. In previous work we have analyzed three phases of tolerance induction characterized by T cell activation, apoptosis, and anergy in both normal mice and spontaneously autoimmune 1pr strain. In general, these results indicate that tolerance induction in vivo involves multiple mechanisms. The focus of Aims 1 and 2 of this proposal is to analyze the mechanisms regulating apoptosis and maintaining anergy. We have adapted techniques to identify and isolate activated and apoptotic T cells in T cell receptor transgenic mice during tolerance induction that permit both phenotypic and functional analysis. These results should provide important insight into the mechanisms of T cell tolerance induction. Defective tolerance promotes autoimmune disease. In Aim 3 we will investigate the role of defective apoptosis in the pathogenesis of autoimmunity. Our preliminary results indicate that expression of the T cell receptor beta chain transgene inhibits T cell activation with aging and thus prevents autoimmunity. Based on these results, we propose an exciting model of 1pr autoimmunity using T cell receptor alpha beta transgenic mice which can be experimentally manipulated by exogenous antigen. This permits initiating and stopping the autoimmune process at pre determined time points. Our model should provide a powerful tool to investigate both apoptosis and the accumulation of atypical double negative T cells in the pathogenesis of autoimmunity.